2. Academic Validation
  3. Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents

Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents

  • J Med Chem. 2014 Jul 24;57(14):6008-18. doi: 10.1021/jm5003588.
Mei-Juan Wang 1,  Ying-Qian Liu,  Ling-Chu Chang,  Chih-Ya Wang,  Yong-Long Zhao,  Xiao-Bo Zhao,  Keduo Qian,  Xiang Nan,  Liu Yang,  Xiao-Ming Yang,  Hsin-Yi Hung,  Jai-Sing Yang,  Daih-Huang Kuo,  Masuo Goto,  Susan L Morris-Natschke,  Shiow-Lin Pan,  Che-Ming Teng,  Sheng-Chu Kuo,  Tian-Shung Wu,  Yang-Chang Wu,  Kuo-Hsiung Lee
Affiliations

Affiliation

  • 1 School of Pharmacy, Lanzhou University , Lanzhou 730000, PR China.
PMID: 25003995 DOI: 10.1021/jm5003588
Abstract

Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I Inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an Anticancer clinical trial candidate.

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